The experiments outlined in this proposal will investigate the resolution of cell death after damage to the central nervous system, i.e., the process in which dying neurons are targeted and removed by phagocytic cells. Microscopic studies are proposed after visual cortex lesions in both developing and mature rats in order to define the cellular participants in this processes with regard to the type of nonneuronal cell (macrophage, microglia) that targets the degenerating neuron. Such a study, which applies electron microscopic immunocytochemical, and immunohistochemical procedures, is expected to give insight into the differences in the efficiency by which cell death is resolved in the developing versus mature visual system. We will also determine the type of cell death (apoptotic or necrotic) displayed by axotomized dorsal lateral geniculate neurons, because this may provide important clues as to the nature of the signals that emanate from the dying cells to attract phagocytic cells and trigger phagocytosis. These signals will then be more directly investigated in a controlled in vitro environment. Diffusible agents will be identified and initially characterized using a sensitive two-chamber chemotactic assay in which thalamic slices (containing dLGN neurons in various stages of degeneration) are presented to either resident or circulating macrophages. Membrane-mediated responses of macrophages to injured neurons are also indicated after lesions to the CNS and these will be investigated using specific binding assays. It is hoped that these studies will provide basic information about an important component of the CNS response to lesions and thereby complement a rational therapeutic strategy aimed at recovery of function.